JPH0119A - Renal function improving agent - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

[Detailed description of the invention] (Technical field) The present invention relates to a novel renal function improving/diuretic agent.

(Prior art) 2-(4-methoxyphenyl)-3-acetoxy-5-
(2-(dimethylamino)ethyl-8-chloro-2,
3-dihydro-1,5-benzothiazepine-4 (5H)
-one or its pharmacologically acceptable acid addition salt is known to have excellent antihypertensive action and cerebral/coronary vasodilatory action [JP-A-59-225174].

(Structure and effects of the invention) The present invention provides 2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepine) -4
The present invention relates to a renal function improving/diuretic agent containing (5H)-one or a pharmacologically acceptable acid addition salt thereof (hereinafter abbreviated as 8-chloro-benzothiazepine compound) as an active ingredient.

The above-mentioned 8-chloro-benzothiazepine compound, which is the active ingredient of the present invention, has excellent renal function improving effects and diuretic effects.

For example, in both cases of ischemic rat acute renal failure induced by clamping the rat renal artery for 30 minutes and glycerol-induced rat acute renal failure induced by intramuscular administration of glycerol in rats,
Similar to human acute renal failure, blood urea nitrogen and creatinine levels increase abnormally, but the 8-chloro-benzothiazepine compound, which is the active ingredient of the present invention, has an excellent property of significantly improving these values. be effective. In addition, when rats (SHR3P) with 5 strokes and spontaneous hypertension (SHR3P) are fed a salt-containing diet, renal damage (azotemia) similar to chronic renal failure occurs, and lesions in the renal parenchymal tissue (e.g., urinary However, when the 8-chloro-benzothiazepine compound, which is the active ingredient of the present invention, is administered, it has an excellent effect of preventing these renal tissue lesions. Since the drug of the present invention exhibits such an effect, it can be used as a prophylactic/therapeutic agent for renal failure.

Furthermore, when the 8-chloro-benzothiazepine compound of the present invention is orally administered to spontaneously hypertensive patients (S) (R), it does not affect potassium excretion, urine volume, and sodium ion content in urine. The drug of the present invention can be used as a diuretic without the risk of hypokalemia because it exhibits the excellent effect of increasing and excreting both chloride and chloride ions.

The renal function improving/diuretic agent of the present invention can be used by either oral or parenteral administration. When used for oral administration, the 8-chloro-benzothiazepine compound of the present invention can be used as a pharmaceutical preparation, either as such or with a pharmaceutical carrier such as an excipient, a binder, a disintegrant, a lubricant, etc., suitable for oral administration. Can be done. Such pharmaceutical carriers include, for example, starch, lactose, glucose, gelatin, sorbitol, tragacanth, polyvinylpyrrolidone, C.J.
Sugar, corn starch, polyethylene glycol, talc, potassium phosphate, magnesium stearate, and other conventional excipients, binders, disintegrants, lubricants, and the like can be suitably used.

Further, the dosage form may be a solid preparation such as a tablet, capsule, granule, microcapsule, or suppository, or a liquid preparation such as a solution, suspension, or emulsion. On the other hand, when used parenterally, the renal function improving/diuretic agent of the present invention is preferably used as an injection, and examples of solvents for this include distilled water for injection, physiological saline, vegetable oil, propylene glycol, etc. etc., and may further contain safe solubilizing agents, buffers, stabilizers, etc.

The 8-chloro-benzothiazepine compound, which is the active ingredient of the present invention, can be used as a free base or as a pharmacologically acceptable acid addition salt thereof. Examples of pharmacologically acceptable acid addition salts include inorganic acid addition salts such as hydrochloric acid-1 hydrobromide, hydroiodide, perchlorate, sulfate, and phosphate; oxalate; Examples include organic acid addition salts such as maleate, fumarate, tartrate, and methanesulfonate.

The renal function improving/diuretic agent of the present invention varies depending on the type of disease, patient's age, weight, severity of symptoms, administration route, etc., but the dosage of the 8-chloro-benzothiazepine compound, which is the active ingredient, is Usually 0.05 to 1 per day for adults
00+ng/kg, preferably 0゜1~30mg/
kg, particularly preferably 0.1 to LoffIg/kg
It is appropriate to use it so that

As mentioned above, the renal function improving/diuretic agent of the present invention significantly improves abnormalities in blood urea nitrogen and creatinine levels in renal failure states, and also completely prevents lesions in renal parenchymal tissue in chronic renal failure. Therefore, it can be used for the treatment and prevention of renal failure caused by glomerulonephritis, nephrotic syndrome, nephrosclerosis, renal tubular disorder, renal ischemia, etc.

In addition, the renal function improving/diuretic agent of the present invention increases urine volume, sodium ion content, and chloride ion content without affecting potassium excretion, so it can be used as a diuretic without the risk of hypokalemia. , can be used to treat renal failure, etc.

In addition, since the 8-chloro-benzothiazepine compound, which is the active ingredient of the present invention, has two asymmetric carbon atoms in the molecule, it has two stereoisomers (i.e., cis and trans isomers) or 4-chlorobenzothiazepine compounds. Optical isomers of a species (i.e. (+)-cis, (
-)-cis, (+)-)cis and (-)-trans isomers). Although any of these isomers and mixtures thereof can be used for the purposes of the present invention, for boat fishing it is preferred to use the cis isomer.

Experimental Example 1 [Effect on ischemic acute renal failure] [Experimental method] Male and female SD rats (Group 1) that had been fasted overnight were placed under ventoparbital sodium anesthesia, the right renal artery and vein were ligated, and the left renal artery was ligated. Clamp with a cleanser for 30 minutes. In order to investigate the effect of the drug of the present invention on acute renal failure induced under such experimental conditions, the drug administration group was given (+
)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl-8-chloro-2,3-dihydro-1,5-benzothiazepine-
4(5H)-one maleate in saline was injected via the catheter into the tail vein at a rate of 20 μg/kg per minute.

On the other hand, control group (acute renal failure rats without drug administration)
and in the healthy group (the left renal artery was not clamped), physiological saline was injected through the tail vein at a rate of 2.6 wrl/hr.

Subsequently, urine was collected for 24 hours under ad libitum water intake and ad libitum feeding, and then laparotomy was performed under anesthesia to collect blood from the abdominal aorta, and biochemical tests were performed on the plasma separated from the blood and the collected urine.

<result> The results are shown in Table 1 below.

As is clear from Table 1, the plasma urea nitrogen level and plasma creatinine level increased after 24 hours in the control group compared to the healthy group, and the glomerular filtration value (taleatinine clearance) and urine osmolarity decreased. In addition, the NAG index and sodium excretion rate, which indicate renal tubular damage, increased, but it is clear that these changes, which indicate renal dysfunction, were suppressed in the drug administration group.

Experimental Example 2 [Effect on glycerol-induced acute renal failure] Experimental method> Male and female SD rats, 7 weeks old, deprived of water for 24 hours, group 4 to
5 animals) with 10ml of 5oz glycerol-physiological saline solution.
/kg intramuscularly into the thigh.

In order to investigate the effect of the drug of the present invention on acute renal failure induced under such experimental conditions, the drug administration group was given (+)-cis-2-(
4-methoxyphenyl)-3-acetoxy-5-(2-
An aqueous solution of (dimethylamino)ethyl-8-chloro-2,3-dihydro-1°5-benzothiazepine-4(5H)-one maleate was added at 10 mg/kg, 3
Oral administration was carried out at a fixed time every day to give a dose of 0 mg/kg, and the same oral administration was carried out after administration of glycerol.

On the other hand, water was orally administered to the control group instead of the sample solution.

Three days after the administration of glycerol, the rats in both groups were subjected to laparotomy under ether anesthesia, blood was collected from the abdominal aorta, and the serum separated from the blood was subjected to biochemical tests.

Results〉 The results are shown in Table 2 below.

The above table shows that in the control group, there was a marked increase in serum urea nitrogen and creatinine levels, which are characteristic of acute renal failure, but in the drug administration group, these values decreased in a dose-dependent manner. It is clear that this drug suppresses the onset of acute renal failure.

Experimental Example 3 [Effect on rats with chronic renal failure] [Experimental method] Spontaneous hypertensive rats with 5 strokes (abbreviation: 5HR3P,
(13 weeks old, 8 animals in - group) were fed 8x salt-added powdered feed for 3 weeks. In order to investigate the effect of the drug of the present invention on chronic renal failure induced under such conditions, the drug administration group received (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2 -(dimethylamino)ethyltwo 8
-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate at 1000 ppr
The control group was fed an 8χ salt-added powdered diet for 3 weeks, and the control group was fed an 8χ salt-added powdered diet for 3 weeks.

After rearing, the abdomen was opened under ether anesthesia, blood was collected from the abdominal aorta, and then sacrificed.

Biochemical tests were performed on the collected blood, and histopathological tests on the kidneys were performed.

Results〉 The results are shown in Table 3 below.

In the above table, Hon, Δ and Mu represent the following.

* HP <0.01 Allantoic fluid △: Renal tubules with decreased staining of epithelial cells, narrowing of the lumen, and tortuous basement membrane are observed in an area of 30% or more of the renal cross section and less than 60χ .

M: The above changes are observed in 60% or more of the renal cross section.

2.1 Hi△: Glomeruli with snare collapse or sclerosis are observed in 30% or more and less than 60χ of the torsion glomeruli on the section.

M: 60% or more of the above changes are observed.

l Emperor's madness △: Protein casts are observed scattered in the cortex.

M: Protein casts are widely observed in the cortex.

From the above table, it can be seen that in the control group, tubular atrophy, glomerular loop collapse,
While histopathological changes such as induration and protein casts indicating proteinuria were noticeable, it is clear that no such altered renal lesions were observed in the drug-administered group.

Furthermore, the control group had a high creatinine value, clinically indicating renal failure, but such a phenomenon was not observed in the group administered with the drug of the present invention.

Experimental Example 4 [Effect on electrolyte balance and urine output] [Experimental method] Male SHR (body weight: 335-415 g, -
2.5++d/100g of physiological saline was orally administered to a group of 10 animals, and 1 hour later, (+)-cis-2-(4-methoxyphenyl)- was adjusted to a predetermined concentration with physiological saline.
3-acetoxy-5-(2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate was administered orally.

On the other hand, the control group received physiological saline instead of the sample solution.
．． 5y/100g was administered orally. Immediately thereafter, the animals were placed in a urine collection cage and left for 5 hours, and the urine excreted during this time was collected. After measuring urine volume, urinary electrolytes (sodium ions, potassium ions, chloride ions)? Measure j1 degree,
Electrolyte excretion was determined.

Results〉 The results are shown in Table 4.

From Table 4, compared to the control group, the IOB/kg drug administration group had a 73% lower urine volume, 96% lower sodium ion excretion, and
It is clear that it increases chloride ion excretion by 77%, does not affect potassium ion excretion, significantly increases the urinary Na/to ratio, and improves electrolyte metabolism.

Example 1 (Tablet) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl2-8
-chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate
45.0 g corn starch 20.
1g Lactose 82.4g Polyvinylpyrrolidone 3.0g Crystalline Cellulose 38.0g Magnesium Stearate 1.5g Total 190.0
g The drug, lactose, and cornstarch are mixed with an alcoholic solution of polyvinylpyrrolidone, cross-wire granulated by a wet granulation method, and then dried to form granules.

Then, magnesium stearate and crystalline cellulose were added, and tablets with a diameter of 8 mm and a weight of 190 mg were made using a tablet machine.

Example 2 (Injection) (+)-cis-2-(4-methoxyphenyl)-3-acetoxy-5-(2-(dimethylamino)ethyl]-8
-Chloro-2,3-dihydro-1,5-benzothiazepine-4(5H)-one maleate (10 g) in distilled water for injection (2Ii)! dissolve in

This solution is filtered through a membrane filter with a pore size of 0.22 μm, and 2 ml each is dispensed into ampoules under aseptic operation, and the ampoules are melt-sealed to give an injection.

Claims (3)

[Claims] (1) 2-(4-methoxyphenyl)-3-acetoxy-5-[2-(dimethylamino)ethyl]-8-chloro-2,3-dihydro-1,5-benzothiazepine-4(
A renal function improving/diuretic agent containing 5H)-one or a pharmacologically acceptable acid addition salt thereof as an active ingredient. (2) The drug according to claim 1, which is a prophylactic/therapeutic agent for renal failure. (3) The drug according to claim 1, which is a diuretic.